4egc

Structural highlights

Disease

[SIX1_HUMAN] Autosomal dominant non-syndromic sensorineural deafness type DFNA;BOR syndrome;Branchiootic syndrome. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. Defects in SIX1 could be a cause of branchiootorenal syndrome (BOR). BOR is an autosomal dominant disorder manifested by various combinations of preauricular pits, branchial fistulae or cysts, lacrimal duct stenosis, hearing loss, structural defects of the outer, middle, or inner ear, and renal dysplasia. Associated defects include asthenic habitus, long narrow facies, constricted palate, deep overbite, and myopia. Hearing loss may be due to mondini type cochlear defect and stapes fixation. Penetrance of BOR syndrome is high, although expressivity can be extremely variable.^{[1] [2]}

Function

[MALE_ECOLI] Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.[SIX1_HUMAN] Transcription factor that is involved in the regulation of cell proliferation, apoptosis and embryonic development (By similarity). Plays an important role in the development of several organs, including kidney, muscle and inner ear (By similarity). Depending on context, functions as transcriptional repressor or activator (By similarity). Lacks an activation domain, and requires interaction with EYA family members for transcription activation (PubMed:15141091). Mediates nuclear translocation of EYA1 and EYA2 (PubMed:19497856). Binds the 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 element in the MYOG promoter and CIDEA enhancer (PubMed:27923061, PubMed:23435380, PubMed:15141091, PubMed:19497856). Regulates the expression of numerous genes, including MYC, CCND1 and EZR (By similarity). Acts as activator of the IGFBP5 promoter, probably coactivated by EYA2 (By similarity). Repression of precursor cell proliferation in myoblasts is switched to activation through recruitment of EYA3 to the SIX1-DACH1 complex (By similarity). During myogenesis, seems to act together with EYA2 and DACH2 (By similarity). Regulates the expression of CCNA1 (PubMed:15123840). Promotes brown adipocyte differentiation (By similarity).[UniProtKB:Q62231]^{[3] [4] [5] [6] [7]}

References

1. ↑ Ruf RG, Xu PX, Silvius D, Otto EA, Beekmann F, Muerb UT, Kumar S, Neuhaus TJ, Kemper MJ, Raymond RM Jr, Brophy PD, Berkman J, Gattas M, Hyland V, Ruf EM, Schwartz C, Chang EH, Smith RJ, Stratakis CA, Weil D, Petit C, Hildebrandt F. SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. Proc Natl Acad Sci U S A. 2004 May 25;101(21):8090-5. doi:, 10.1073/pnas.0308475101. Epub 2004 May 12. PMID:15141091 doi:http://dx.doi.org/10.1073/pnas.0308475101
2. ↑ Patrick AN, Schiemann BJ, Yang K, Zhao R, Ford HL. Biochemical and functional characterization of six SIX1 Branchio-oto-renal syndrome mutations. J Biol Chem. 2009 Jul 31;284(31):20781-90. doi: 10.1074/jbc.M109.016832. Epub, 2009 Jun 4. PMID:19497856 doi:http://dx.doi.org/10.1074/jbc.M109.016832
3. ↑ Coletta RD, Christensen K, Reichenberger KJ, Lamb J, Micomonaco D, Huang L, Wolf DM, Muller-Tidow C, Golub TR, Kawakami K, Ford HL. The Six1 homeoprotein stimulates tumorigenesis by reactivation of cyclin A1. Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6478-83. doi:, 10.1073/pnas.0401139101. Epub 2004 Apr 26. PMID:15123840 doi:http://dx.doi.org/10.1073/pnas.0401139101
4. ↑ Ruf RG, Xu PX, Silvius D, Otto EA, Beekmann F, Muerb UT, Kumar S, Neuhaus TJ, Kemper MJ, Raymond RM Jr, Brophy PD, Berkman J, Gattas M, Hyland V, Ruf EM, Schwartz C, Chang EH, Smith RJ, Stratakis CA, Weil D, Petit C, Hildebrandt F. SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. Proc Natl Acad Sci U S A. 2004 May 25;101(21):8090-5. doi:, 10.1073/pnas.0308475101. Epub 2004 May 12. PMID:15141091 doi:http://dx.doi.org/10.1073/pnas.0308475101
5. ↑ Patrick AN, Schiemann BJ, Yang K, Zhao R, Ford HL. Biochemical and functional characterization of six SIX1 Branchio-oto-renal syndrome mutations. J Biol Chem. 2009 Jul 31;284(31):20781-90. doi: 10.1074/jbc.M109.016832. Epub, 2009 Jun 4. PMID:19497856 doi:http://dx.doi.org/10.1074/jbc.M109.016832
6. ↑ Patrick AN, Cabrera JH, Smith AL, Chen XS, Ford HL, Zhao R. Structure-function analyses of the human SIX1-EYA2 complex reveal insights into metastasis and BOR syndrome. Nat Struct Mol Biol. 2013 Feb 24. doi: 10.1038/nsmb.2505. PMID:23435380 doi:http://dx.doi.org/10.1038/nsmb.2505
7. ↑ Brunmeir R, Wu J, Peng X, Kim SY, Julien SG, Zhang Q, Xie W, Xu F. Comparative Transcriptomic and Epigenomic Analyses Reveal New Regulators of Murine Brown Adipogenesis. PLoS Genet. 2016 Dec 6;12(12):e1006474. doi: 10.1371/journal.pgen.1006474., eCollection 2016 Dec. PMID:27923061 doi:http://dx.doi.org/10.1371/journal.pgen.1006474
8. ↑ Patrick AN, Cabrera JH, Smith AL, Chen XS, Ford HL, Zhao R. Structure-function analyses of the human SIX1-EYA2 complex reveal insights into metastasis and BOR syndrome. Nat Struct Mol Biol. 2013 Feb 24. doi: 10.1038/nsmb.2505. PMID:23435380 doi:http://dx.doi.org/10.1038/nsmb.2505